Thesis defense Manon Baudic

About 10% of sudden cardiac deaths (SCD) occur in individuals without ischemic heart disease or structural abnormalities and are considered as primary electrical pathologies, that are often inherited. The genetic origin of electrical pathologies was initially associated with rare mutations with strong effect in the coding regions of the genome. However, some familial studies show variable expressiveness of the pathology and incomplete penetrance of rare variants, suggesting the involvement of modulators. However, the majority of patients with hereditary primary electrical diseases still remain without a molecular diagnosis. One of the current hypotheses is based on the existence of localized mutations in the non-coding regions of the genome.

The application of new sequencing technology allowed us to identify rare variants in these non-coding regions in patient genomes. A new challenge now lies in the annotation and understanding of the molecular mechanisms of these regions at the origin of heart disease.

Thus, from 7 families presenting with a complex heart disease associated electrical disorders to developmental anomalies, we identified rare overlapping deletions (15-330kb) located in a gene desert in the 4q25 region. In this international collaboration, I focused on characterizing the epigenetic mechanism and molecular consequences underlying these deletions. This work led to the study of a murine model as well as an isogenic hiPSC-CM model. Thanks to these models, a dysregulation of the expression of the PITX2 gene was highlighted, caused by the deletion of a CTCF binding site at the origin of a 3D remodeling of the chromatin.

In parallel, I applied my expertise in functional genomic annotation of non-coding regions to Brugada syndrome (BrS), for which we carried out an association study with 2820 cases. This work allowed the identification of 19 frequent non-coding variants-loci associated with BrS. The functional genomic annotation shows their interactions with target genes and for some, a regulation of their expression. Whole genome sequencing of 354 index cases also allowed me to identify a rare deletion of a regulatory region at the origin of BrS

In conclusion, this work combining genetic, epigenetic and functional approaches clarifies the complex genetic architecture of rhythmic heart disease and opens the way for a better risk stratification of SCD.